Elsevier

Journal of Controlled Release

Volume 70, Issue 3, 23 February 2001, Pages 375-382
Journal of Controlled Release

Preparation of desmopressin-containing liposomes for intranasal delivery

https://doi.org/10.1016/S0168-3659(00)00369-2Get rights and content

Abstract

The loading and leakage characteristics of the desmopressin-containing liposomes and the effect of liposomes on the nasal mucosa permeation and antidiuresis of desmopressin were investigated. Higher loading efficiency of desmopressin for positively charged liposomes than negatively charged liposomes was obtained, and neutral liposomes resulted in a similar loading efficiency as that of positively charged liposomes. Greater leakage of desmopressin from negatively charged liposomes than from positively charged and neutral liposomes was shown. The increase of permeability of desmopressin through the nasal mucosa indicated positively charged liposomes>negatively charged liposomes>solution. It was suggested that the enhanced contact time of positively charged liposomes with negatively charged nasal mucosa led to a high local desmopressin concentration on the penetration site to promote an effective penetration of desmopressin through the nasal mucosa. The desmopressin antidiuresis result after intranasal administration was in good agreement with the permeability result in the order of positively charged liposomes>negatively charged liposomes>solution. One of the mechanisms for the explanation of the best result on the enhancement of antidiuresis for positively charged liposomes may be the bioadhesive effect of the liposomes on the negatively charged nasal mucosa.

Introduction

Desmopressin, a synthetic analog of vasopressin, is used in the treatment of central diabetes insipidus, nocturnal enuresis, mild forms of hemophilia A and von Willebrand disease [1]. Desmopressin is effective after intranasal administration but with poor absorption, and the bioavailability is low in the range from 2.0 to 11.3% [2], [3], [4]. Attempts have been made to enhance desmopressin nasal absorption by using several techniques such as viscous formulation [5], [6], [7], metered-dose nasal spray instead of nose drops [8], lipophilic prodrug formulation [9], and bioadhesive delivery system [7], [10]. Liposome delivery system was found to enhance nasal penetration and absorption of calcitonin or insulin [11], [12]. This was attributed to the increasing nasal retention of peptides [11]. Liposomes also provided protection of the entrapped peptides from enzymatic degradation [13], [14] and disrupted the mucosal membrane to increase absorption of peptides [15]. However, little work has been done on liposomes used as a delivery system for desmopressin in intranasal administration. In the present study, we reported the loading and leakage characteristics of desmopressin-containing liposomes and the effect of liposomes on desmopressin permeation through the rabbit nasal mucosa and antidiuresis in rats after intranasal administration. In terms of charge characteristics of liposomes, we compared their results on the enhancement of antidiuresis.

Section snippets

Materials

Desmopressin was obtained from Penta Inc. (USA). Dioleoylphosphatidylcholine (DOPC) and cholesterol (C) were purchased from Sigma Chemical Co. (USA). Stearylamine (S) and phosphatidylserine (PS) used as positively and negatively charged inducing agents were obtained from Pharmacia P-L Chemicals (Sweden) and Sigma Chemical Co. (USA), respectively. The buffer solutions used for the preparation of liposomes were phosphate-buffered saline (PBS, pH 7.4) and 0.9% sodium chloride solution (pH 4.0,

Results and discussion

The loading efficiency of desmopressin in liposomes against added concentrations of desmopressin during the preparation of liposomes is shown in Fig. 1. The effect of charge characteristics of liposomes on loading efficiency demonstrated that for all liposome preparations the loading efficiency increased with increasing the added concentration of desmopressin until a plateau loading efficiency was attained. Similar results of loading efficiency were obtained for positively charged and neutral

Conclusion

From the results of this study, it seems that liposomes have a good potential as an intranasal delivery system for desmopressin. Positively charged liposomes were able to produce an increase in penetration of desmopressin through the nasal mucosa and a significant enhancement of antidiuresis of desmopressin after intranasal administration. One of the possible mechanisms is the enhanced attachment of positively charged liposomes on the nasal mucosa.

Acknowledgements

This work was supported by VGH89-375.

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